Dapsone (4,4'-diaminodiphenyl sulfone, DDS) and its repository form, acedapsone (4,4'-diacetamidodiphenyl sulfone, DADDS), have emerged as the most efficacious agents for treatment of leprosy. Both DDS and DADDS (through hydrolysis to DDS) exhibit high activity and low orders of toxicity at effective doses, and the emergence of organisms resistant to these drugs during therapy is infrequent. They are being administered to many of the estimated 10 million individuals suffering from leprosy throughout the world. Therefore, a clear understanding of the disposition and metabolic fate of these compounds is needed to provide a rational basis for their most optimal use. Recently, the antibiotic rifampin has been shown to be highly active in primary treatment and in the treatment of DDS-resistant leprosy. In earlier work, we developed procedures for the accurate measurement of DDS, its monoacetylated derivative, MADDS, and DADDS in plasma; and DDS and MADDS and their conjugates in urine. Application of these techniques to different racial groups has shown that DDS is acetvalated polymorphically. Of the two species known to act as hosts for the in vivo multiplication of M. leprae and readily available to us, we found that the rat was a better model of man than was the mouse, for metabolic studies of DDS. Also, we have established that the minimal inhibitory concentration (MIC) of DDS for M. leprae in rats is approximately 3 ng/ml of plasma, nearly identical to recent determinations of the MIC of DDS for M. leprae in mice. Tissue levels of DDS and MADDS in mice and rats fed DDS were found to approximately parallel plasma levels. Our objectives are to establish the relationship between plasma and tissue levels in leprosy patients receiving DDS; to expand our capabilities for measuring DDS and its metabolites in urine and plasma to define completely the metabolic ptterns of DDS in man; and to initiate studies on the possible interactions between rifampin and DDS in man. BIBLIOGRAPHIC REFERENCES: J.H. Peters, G. R. Gordon, J. T. Biggs, Jr., and L. Levy. The disposition of dapsone and monoacetyl dapsone in the dog. Proc. Soc. Exp. Biol. Med., 148, 251-255 (1975).